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Title: Effects of rigidity on the selectivity of protein kinase inhibitors

Abstract

Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. As such, here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.

Authors:
ORCiD logo [1];  [1];  [2];  [1];  [1];  [1];  [3];  [2]; ORCiD logo [4]
  1. Univ. of Southern California, Univ. Park, Los Angeles, CA (United States)
  2. Mount Sinai Hospital, Toronto, ON (Canada)
  3. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
  4. Univ. of Southern California, Univ. Park, Los Angeles, CA (United States); Univ. of Southern California, Los Angeles, CA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Science Foundation (NSF); National Institutes of Health (NIH); Canadian Cancer Society Research Institute (CCSRI); Canadian Institutes of Health Research (CIHR); TD Bank Postdoctoral Fellowship
OSTI Identifier:
1431357
Grant/Contract Number:  
CHE-1455306; R01DE026003; 704116; FDN143277; P41 GM103403; S10 RR029205
Resource Type:
Accepted Manuscript
Journal Name:
European Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 146; Journal Issue: C; Journal ID: ISSN 0223-5234
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Kinase inhibitors; Selectivity; Ring closure; Rigidification; Abl; BRAF

Citation Formats

Assadieskandar, Amir, Yu, Caiqun, Maisonneuve, Pierre, Liu, Xu, Chen, Ying-Chu, Prakash, G. K. Surya, Kurinov, Igor, Sicheri, Frank, and Zhang, Chao. Effects of rigidity on the selectivity of protein kinase inhibitors. United States: N. p., 2018. Web. https://doi.org/10.1016/j.ejmech.2018.01.053.
Assadieskandar, Amir, Yu, Caiqun, Maisonneuve, Pierre, Liu, Xu, Chen, Ying-Chu, Prakash, G. K. Surya, Kurinov, Igor, Sicheri, Frank, & Zhang, Chao. Effects of rigidity on the selectivity of protein kinase inhibitors. United States. https://doi.org/10.1016/j.ejmech.2018.01.053
Assadieskandar, Amir, Yu, Caiqun, Maisonneuve, Pierre, Liu, Xu, Chen, Ying-Chu, Prakash, G. K. Surya, Kurinov, Igor, Sicheri, Frank, and Zhang, Chao. Wed . "Effects of rigidity on the selectivity of protein kinase inhibitors". United States. https://doi.org/10.1016/j.ejmech.2018.01.053. https://www.osti.gov/servlets/purl/1431357.
@article{osti_1431357,
title = {Effects of rigidity on the selectivity of protein kinase inhibitors},
author = {Assadieskandar, Amir and Yu, Caiqun and Maisonneuve, Pierre and Liu, Xu and Chen, Ying-Chu and Prakash, G. K. Surya and Kurinov, Igor and Sicheri, Frank and Zhang, Chao},
abstractNote = {Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. As such, here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.},
doi = {10.1016/j.ejmech.2018.01.053},
journal = {European Journal of Medicinal Chemistry},
number = C,
volume = 146,
place = {United States},
year = {2018},
month = {1}
}

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